Fluorinated benzodiazepins

ABSTRACT

New fluorinated benzodiazepins are described. They are expressed by the following general formula: ##STR1## wherein A 1  and A 2  are the same or different groups, each expressed by one of the following general formulas ##STR2## R 2  being a hydrogen atom, aliphatic hydrocarbon group, fluorine-substituted aliphatic hydrocarbon group, aminoalkyl, N,N-dialkylaminoalkyl, or alkylsulfonylalkyl group and R 3  a hydrogen atom, aliphatic or aromatic hydrocarbon group, halogen-substituted aliphatic or aromatic hydrocarbon group, while R 1  is a hydrogen atom, aliphatic or aromatic hydrocarbon group, fluorine-substituted aliphatic or aromatic hydrocarbon group and X is a hydrogen atom, aliphatic hydrocarbon group, fluorine-substituted aliphatic hydrocarbon group, halogen atom, nitro group or the like.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to new fluorinated benzodiazepins.

2. Description of the Prior Art

Some mono-fluorinated compounds are known to exhibit usefulphysiological activities.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of the present invention to provide new and usefulfluorinated benzodiazepins. This object is accomplished according to theinvention by fluorinated benzodiazepins of the formula. ##STR3## whereinA¹ and A² are the same or different groups, each expressed by one of thefollowing general formulas ##STR4## R² being a hydrogen atom, aliphatichydrocarbon group, fluorine-substituted aliphatic hydrocarbon group,aminoalkyl, N,N-dialkylaminoalkyl, or alkylsulfonylalkyl group and R³ ahydrogen atom, aliphatic or aromatic hydrocarbon group,halogen-substituted aliphatic or aromatic hydrocarbon group, while R¹ isa hydrogen atom, aliphatic or aromatic hydrocarbon group,fluorine-substituted aliphatic or aromatic hydrocarbon group and X is ahydrogen atom, aliphatic hydrocarbon group, fluorine-substitutedaliphatic hydrocarbon group, halogen atom, nitro group or the like.

The above fluorinated benzodiazepins are useful as physiologicallyactive substances, such as insecticide and disinfectant, orintermediates to synthesize building blocks of these substances.

Other objects and advantages of the invention will become apparent fromthe following description of embodiments.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the fluorinated benzodiazepins of the invention, the groups A¹ and A²respectively contain a nitrogen atom necessary to form a diazepin ring.Basically, they are provided in one of the following three forms##STR5##

Therefore, there is possible to be a variety of the fluorinatedbenzodiazepins. Among these compounds, preferred is compound of theformula ##STR6##

Among the group R² is preferred a hydrogen atom, alkyl, fluoralkyl,alkenyl, aminoalkyl, N,N-dialkylaminoalkyl, or alkylsulfonylalkyl group,containing up to ten carbon atoms. Examples of such R² are hydrogenatom, methyl, ethyl, propyl, butyl, c-propylmethyl, trifluoroethyl,N,N-diethylaminoethyl, and methylsulfonylethyl groups.

Among the group R³ is preferred a hydrogen atom, alkyl, fluoroalkyl,phenyl, fluorophenyl or chlorophenyl group containing up to ten carbonatoms. The R³ may thus be selected among the alkyl, fluoroalkyl, alkenyland fluoroalkenyl groups cited above for the group R². For example, itmay represent a trifluoromethyl group. Further examples of the R³ arephenyl and other aryl groups which may have floro, chloro and/orfluoroalkyl substituent or substituents. For example, it may be ##STR7##

The group R¹ is preferably a hydrogen atom, alkyl, fluroalkyl, alkenylor fluoroalkenyl group having up to five carbon atoms. The R¹ may thusbe one of the alkyl, fluroalkyl, alkenyl and fluoroalkenyl groups citedabove for the R² and R³ as far as the number of carbon atoms are limitedto five. For example, methyl, ethyl, propyl and butyl groups arepreferable. Further, the group R¹ may be a phenyl, fluorophenyl or otheraryl group, or even an aralkyl group.

It is noted that in the above fluorinated groups, for example, in the"fluoralkyl group" the number of substituent fluorine atoms and theirpositions may be variously changed.

Further, in the above general formula representing the fluorinatedbenzodiazepins of the invention, the substituent X on the benzene ringis preferably one of the alkyl and alkenyl groups having up to fivecarbon atoms as cited above for R¹, for example, methyl group, orhalogen atom, such as chlorine or fluorine atom, nitro group or thelike.

At least having a fluorine atom at the 3-position of their heterocyclicring, the fluorinated benzodiazepins of the invention arephysiologically active and expected to have other properties that arecharacteristic of the fluorinated compound.

The fluorinated benzodiazepins of the invention can be prepared by aprocess defined by a series of reaction formulas as given next. First,hexafluoropropene (CF₃ CF═CF₂) is reacted in a solution of sodiumethoxide in ethanol to form an adduct 1, which is then hydrolized to anester 2 by sulfuric acid or the like. This ester is again reacted in asolution of sodium ethoxide in ethanol for conversion of its CF₃ groupto an ester group to produce fluoromalonic ester 3. The ester 3 isalkylated by the ordinary method to synthesize an alkylated product 4.The α-fluoro-β-diesters 3 and 4 thus prepared can be used for thesynthesis of fluorinated benzodiazepins as mentioned later. ##STR8##

Meanwhile, according to the following series of reaction formulas,trifluoroethene (CHF═CF₂) is reacted with acetyl chloride in presence ofAlCl₃ to form an adduct 5, which is then alcoholized to giveα-fluro-β-ketoester 6 that can be used for synthesis of fluorinatedbenzodiazepins of the invention. ##STR9##

Further, according to the following series of reaction formulas, anadduct 7 and substitution product 8 are produced by the reaction ofhexafluoropropene and diethylammonium and they are hydrolized to anamide 9, which is then reacted with R³ MgBr wherein R³ is one of thepreferable groups as cited above for R³ to produce a ketone 10 that canbe alcoholized by the ordinary method to α-fluorobenzoylacetic ester 11.##STR10##

The above products 3, 4, 6 and 11 can be used to synthesize fluorinatedbenzodiazepins of the invention by methods as described below.

Synthesis of 1H-3-fluoro-1,5-benzodiazepin-2,4(3H,5H)-dione 12

O-phenylenediamine and fluoromalonic ester 3 are dissolved in a solutionof sodium ethoxide in ethanol and the solution is refulxed for 1 to 10hours for a reaction to produce a benzodiazepin 12 in high yieldaccording to the following reaction formula. The alkylated product 4 offluoromalonic ester 3 is likewise reacted to give the correspondingbenzodiazepin 12 in high yield. ##STR11##

Solvents applicable for this reaction can be aprotic polar solvent, forexample, dimethylformamide, dimethylsulfoxide and sulfolane whereinbases such as Na, K, NaH are used. Reaction temperature can be 50° to150° C. and reaction pressure can be atmospheric or reduced pressure.

When the R¹ was variously changed in the above reaction, the targetcompound 12 was produced in high yield as the corresponding products aslisted in the following table:

    ______________________________________                                        Product 12 Yield   M.P.    IR (cm.sup.-1)                                                                         .sup.19 FNMR                              R.sup.1                                                                              X       (%)     (°C.)                                                                        (CO) (NH)  ppm (.sup.J H-F)                      ______________________________________                                        H      H       61      >300  1680 3200  132.1d(J39.5)                         H      CH.sub.3 --                                                                           72      >300  1670 3260  130.0d(J39.5)                         H      Cl      44      >300  1690 3340  129.5d(J39.5)                         H      NO.sub.2                                                                              52       262  1690 3350  119.5d(J39.5)                         CH.sub.3 --                                                                          H       59       245  1680 3200   78.0q(J20.7)                         C.sub.2 H.sub.5 --                                                                   H       62       283  1660 3170   87.5t(J19.8)                         C.sub.4 H.sub.9 --                                                                   H       48       204  1690 3200   85.5t(J18.8)                         ______________________________________                                    

Further, when reacted with R² Y, wherein R² is one of the groups asmentioned above for such and Y is a halogen atom, for example, I, thebenzodiazepin 12 is readily substituted with a group R² according to thefollowing formula. For example, when reacted with CH₃ I, it ismethylated. A protected and stabilized benzodiazepin derivative 13 canthus be prepared. ##STR12##

Solvents applicable for this reaction can be alcohol such as ethanol aswell as aprotic polar solvent already described. Reaction temperaturecan be 20° to 100° C. and reaction pressure can be atmospheric orreduced pressure. The same benzodiazepin 12 can also be converted toother benzodiazepin 14 or 15 according to the following reactionformulas: ##STR13##

Synthesis of 1H-3-fluoro-4-phenyl-1,5-benzodiazepin-2-one 16

O-phenylenediamine and α-fluorobenzoylacetic ester 11 are put in a mixedsolvent of CH₃ COOH/C₂ H₅ OH and refluxed to form a benzodiazepin 16 inhigh yield (for example, 43 to 65%) according to the following reactionformula. ##STR14##

It is noted that the phenyl group Ph on the heterocyclic ring of theproduct 16 may be a different R³ as mentioned above. For example, abenzodiazepin 17 wherein R³ =CH₃ --, can be prepared by the followingreaction: ##STR15##

Solvent usable for the reactions to produce 16 and 17 can be aproticpolar solvent already described, reaction temperatures can be 50° to150° C. and reaction pressure can be atmospheric.

On the other hand, β-perfluoroalkyl-β-ketoesters 11' and 11" can beprepared by the crossed Claisen condensation according to the followingreaction formulas, which may also be used for synthesis of fluorinatedbenzodiazepins of the present invention. ##STR16##

The present invention will be more clearly understood with reference tothe following examples.

EXAMPLE 1

O-phenylenediamine (1.1 g, 10 mmol) and ethyl fluoromalonate (1.8 g, 10mmol) were added to a solution of sodium ethoxide (0.68 g, 10 mmol) inethanol (10 ml). The mixture was refluxed 5 hours and left to standovernight at room temperature. The solution was then acidified byhydrochloric acid and precipitates were separated by filtration.Recrystallization from acetic acid gave 1.2 g of a white crystallineproduct of a melting point above 300° C. (61%).

EXAMPLE 2

P-chloro-o-phenylenediamine (1.5 g, 10 mmol) and ethyl fluoromalonate(1.8 g, 10 mmol) were added to a solution of sodium ethoxide (0.68 g, 10mmol) in ethanol (10 ml). The same process as applied to Example 1 gave1.0 g of a crystalline product of a melting point above 300° C. (44%).

EXAMPLE 3

P-nitro-o-phenylenediamine (1.6 g, 10 mmol) and ethyl fluoromalonate(1.8 g, 10 mmol) were added to a solution of sodium ethoxide (0.68 g, 10mmol) in ethanol (10 ml). The same process as applied to Example 1 wasrepeated except that methanol was used for recrystallization. There wasproduced 1.3 g of crystalline product of a melting point 262° (52%).

EXAMPLE 4

P-methyl-o-phenylenediamine (1.3 g, 10 mmol) and ethyl fluoromalonate(1.8 g, 10 mmol) were added to a solution of sodium ethoxide (0.68 g, 10mmol) in ethanol (10 ml). The same process as applied to Example 1 wasrepeated except that methanol was used for recrystallization. There wasproduced 1.5 g of a crystalline product of a melting point above 300° C.(72%).

EXAMPLE 5

O-phenylenediamine (1.1 g, 10 mmol) and ethyl 2-fluoro-2-methylmalonate(1.95 g, 10 mmol) were added to a solution of sodium ethoxide (0.68 g,10 mmol) in ethanol (10 ml). The mixture was refluxed 5 hours and leftto stand overnight at room temperature. The solution was then acidifiedby hydrochloric acid and precipitates were separated by filtration.Recrystallization from methanol gave 1.25 g of a crystalline product ofa melting point above 245° C. (59%).

EXAMPLE 6

In Example 5, ethyl 2-fluoro-2-ethylmalonate (2.15 g, 10 mmol) was usedin place of ethyl 2-fluoro-2-methylmalonate. The same procedure asExample 5 were performed. Recrystallization from ethanol gave a productof melting point 283° C. in a yield of 62%.

EXAMPLE 7

O-phenylenediamine (1.1 g, 10 mmol) and ethyl 2-fluoro-2-butylmalonate(2.35 g, 10 mmol) were added to a solution of sodium ethoxide (0.68 g,10 mmol) in ethanol (10 ml). The same process as applied to Example 5was repeated except that water was used for recrystallization. There wasgiven 1.25 g of a crystalline product of a melting point 204° C. (48%)

EXAMPLE 8

Methyl iodide (2.9 g, 20 mmol) was added dropwise in half an hour to asolution of 1H-3-fluoro-1,5-benzodiazepin-2,4(3H,5H)-dione (1.95 g, 10mmol) and sodium ethoxide (0.68 g, 10 mmol) in ethanol (20 ml). Themixture was refluxed 3 hours. After cooling, it was acidified andprecipitates were separated by filtration. Recrystallization frommethanol gave 1.2 g of a needle-like crystalline product of a meltingpoint above 300° C. (55%). This product showed the following analyticaldata.

Anal. Found: C,59.21; H,4.87; N,12.74%. Calcd. for C₉ H₁₁ N₂ O₂ F.C,59.45; H,4.98; N,12.60%.

IRνmax. (KBr) 1722,1700,1600 cm⁻¹. (CO,C=N, stretching).

¹⁹ F NMR δ(neat)+126.o,d,J=45.16 Hz,1F,CHF.

¹ H MNR δ(DMSO-d₆) 3.3,s,6H,2CH₃ ; 5.33, d,J=48.5 Hz, 1H, CHF;7.19,s,4H,Ar--H.

EXAMPLE 9

Ethyl 1,1,1-trifluoro-3-fluoro-acetylacetate (1.85 g, 10 mmol) ando-phenylenediamine (1.1 g, 10 mmol) were added in a mixed solvent (25 mlof ethyl alcohol plus 10 ml of acetic acid). After refluxing 5 hours,solvent was evaporated. Recrystallization of residues from ethanol gave1.85 g of a crystalline product of a melting point 165° C. (80% ).

EXAMPLE 10

Using ethyl 1,1,1-trifluoro-3-fluoro-acetylacetate (1.85 g, 10 mmol) andp-methyl-o-phenylenediamine (2.45 g, 10 mmol), the process of Example 8was repeated. There was thus produced 2.3 g of a crystalline product ofa boiling point 198° C. (95%).

EXAMPLE 11

Using ethyl 1,1,1-trifluoro-3-fluoro-acetylacetate (1.85 g, 10 mmol) andp-chloro-o-phenylenediamine (2.65 g, 10 mmol), the process of Example 8was repeated. There was produced 2.1 g of a crystalline product of amelting point 237° C. (75%).

EXAMPLE 12

O-phenylenediamine (1.08 g, 10 mmol) and trifluorobenzoylacetone (2.0 g,10 mmol) were suspended in acetic acid and heated 3 hours at 80° C.After the mixture cooled down, it was poured into iced water andprecipitates thereby formed were separated by filtration.Recrystallization from chloroform gave 1.9 g of a crystalline product ofa melting point of 208° C. (65%).

Anal. Found: Calcd. for C₁₆ H₁₁ N₂ F₃. C,66.66; H,3.84; N,9.71%.

IR ν max. (KBr) 1598 cm⁻¹. (C=N, stretching).

¹⁹ FδNMR (neat) -13.2s,3F,CF₃.

¹ HδNMR (DMSO-d₆ /CCl₄) 3.4,s,2H,CH₂ ; 7.33-8.0,m,9H,Ar--H. MS (m/e) 288(M⁺)

EXAMPLES 13 to 15

Refluxing of ethyl α-fluorobenzoylacetate (2.25 g, 10 mmol) witho-phenylenediamine (10 mmol) in the mixture of acetic acid and ethanol(25%) for 5 h gave 3-fluoro-1,5-benzodiazepin-2-one derivatives in goodyields as follows. ##STR17## wherein X=H, 4-Me, 4-Cl or NO₂. It is clearthat the first step of this reaction is condensation of carbonyl ketoneand amine by losing water and second step is cyclization of their esterwith another amine by losing ethanol. When used p-CH₃ or p-Clo-phenylenediamine, these were condensed with α-fluorobenzoylacetate,

Products in the above Examples as well as other products that wereproduced according to the invention are listed in Tables 1, 2, and 3together with their physical and analytical data.

It will be evident that various modifications can be made to thedescribed embodiments without departing from the scope of the presentinvention.

                                      TABLE 1                                     __________________________________________________________________________     ##STR18##                                                                                      IR    NMR                     Elementary analysis           Example                                                                            Product M.P. Yield                                                                         (cm.sup.-1)                                                                         19.sub.F                                                                              1.sub.H         theor. values in                                                              parentheses                   No.  R.sup.1                                                                          X  (°C.)                                                                      (%)                                                                              [CO]                                                                             [NH]                                                                             δ ppm(.sup.J HF)                                                                δ ppm     C (%)                                                                              H (%)                                                                              N                   __________________________________________________________________________                                                              (%)                 1    H  H  >300                                                                              61 1680                                                                             3200                                                                             132.1 d(J 39.5)                                                                       5.45 d(CHF), 7.16 s(ArH)                                                                      56.03                                                                              3.65 14.54                                               10.76 s(NH × 2)                                                                         (55.67)                                                                            (3.63)                                                                             (14.43)             4    H  Me >300                                                                              72 1670                                                                             3260                                                                             130.0 d(J 39.5)                                                                       2.20 s(CH.sub.3), 5.45 d(CHF)                                                                 57.60                                                                              4.59 13.32                                               7.07 s(ArH), 10.50 s(NH                                                                       (57.69) 2)                                                                         (4.36)                                                                             (13.43)             2    H  Cl >300                                                                              44 1690                                                                             3340                                                                             129.5 d(J 39.5)                                                                       5.44 d(CHF), 7.11 s(ArH)                                                                      47.03                                                                              2.48 11.99                                               10.30 s(NH × 2)                                                                         (47.20)                                                                            (2.64)                                                                             (12.25)             3    H  NO.sub.2                                                                          262                                                                              52 1690                                                                             3350                                                                             119.5 d(J 39.5)                                                                       5.70 d(CHF), 7.40˜8.10                                                                  44.54)                                                                             2.53 17.29                                               10.45 s(NH × 2)                                                                         (45.19)                                                                            (2.52)                                                                             (17.56)             5    Me H   245                                                                              59 1680                                                                             3200                                                                             78.0 q(J 20.7)                                                                        1.33 d(CH.sub.3), 7.16 s(ArH)                                                                 57.67                                                                              4.57 13.31                                               10.69 s(NH × 2)                                                                         (57.69)                                                                            (4.36)                                                                             (13.45)             6    Et H   283                                                                              62 1660                                                                             3170                                                                             87.5 t(J 19.8)                                                                        0.87 t(CH.sub.3), 1.80 dq(CH.sub.2)                                                           59.34                                                                              4.91 12.56                                               7.23 s(ArH), 10.98 s(NH                                                                       (59.46) 2)                                                                         (4.99)                                                                             (12.61)             7    Bu H   204                                                                              48 1690                                                                             3200                                                                             85.5 t(J 18.8)                                                                        0.66 t(CH.sub.3), 1.00˜1.30                                             m(C.sub.2 H.sub.4)                                                                            62.15                                                                              6.06 11.13                                               1.60 dt(CFC  .sub.--H.sub.2)                                                                  (62.38)                                                                            (6.04)                                                                             (11.19)                                             7.17 s(ArH), 10.90 s(NH                       __________________________________________________________________________                                    × 2)                                

                  TABLE 2                                                         ______________________________________                                         ##STR19##                                                                                                  IR                                              Example                                                                              Product  M.P.    Yield (cm.sup.-1)                                     No.    X        (°C.)                                                                          (%)   [CN]    [CO]  [NH]                              ______________________________________                                         9     H        165     80    1600    1680  3210                              10     CH.sub.3 198     95    1605    1685  3200                              11     Cl       237     75    1600    1690  3200                              ______________________________________                                    

                                      TABLE 3                                     __________________________________________________________________________     ##STR20##                                                                                     IR         NMR                       MS                      Example                                                                            Product                                                                            M.P.                                                                             Yield                                                                             (cm.sup.-1)                                                                              .sup.19 F                                                                             .sup.1 H          (m/e)                   No.  X    (°C.)                                                                     (%) [CN] [CO]                                                                             [NH]                                                                             δ ppm(.sup.J HF)                                                                δ ppm       [M.sup.+ ]              __________________________________________________________________________    13   H    178                                                                              53  1605 1685                                                                             3400                                                                             124 d(41.4)                                                                           5.45 d(CHF), 7.30˜8.20                                                                    254rH)                                                      11.17 s(NH)                               14   CH.sub.3                                                                           188                                                                              61  1620 1690                                                                             3430                                                                             123 d(43.2)                                                                           2.40 s(CH.sub.3), 5.51d(CHF)                                                                    268                                                         7.00˜8.05 m(ArH), 10.93 s(NH)       15   Cl   252                                                                              45  1600 1680                                                                             3420                                                                             122 d(41.8)                                                                           5.56 d(CHF), 7.17˜8.28 m(ArH)                                           11.23 s(NH)                               __________________________________________________________________________

What is claimed is:
 1. A fluorinated benzodiazepin of the formula##STR21## wherein A¹ and A² are the same or different groups, eachexpressed by one of the following formulas ##STR22## R² being a hydrogenatom or a group having up to 10 carbon atoms selected from the groupconsisting of alkyl, alkenyl, fluorine-substituted alkyl,fluorine-substituted alkenyl, aminoalkyl, N,N-dialkylaminoalkyl andalkylsulfonylalkyl, and R³ being a hydrogen atom or a group having up to10 carbon atoms selected from the group consisting of alkyl, alkenyl,phenyl, halogen-substituted alkyl, halogen-substituted alkenyl andhalogen-substituted phenyl, while R¹ is a hydrogen atom, phenyl,fluorine-substituted phenyl or a group having up to 5 carbon atomsselected from the group consisting of alkyl, alkenylfluorine-substituted alkyl and fluorine-substituted alkenyl, and X is ahydrogen atom, halogen atom, nitro group or a group having up to 5carbon atoms selected from the group consisting fo alkyl, alkenyl orfluorine-substituted alkyl and fluorine-substituted alkenyl.
 2. Afluorinated benzodiazepin as claimed in claim 1, wherein said formulathereof is either ##STR23##
 3. A fluorinated benzodiazepin as claimed inclaim 1, wherein said X is a hydrogen atom, alkyl group having up tofive carbon atoms, chlorine or fluorine atom, or nitro group; said R¹ isa hydrogen atom or a group having up to 5 carbon atoms selected from thegroup consisting of alkyl, fluoroalkyl, alkenyl and fluoroalkenyl; saidR² is a hydrogen atom or a group having up to 10 carbon atoms selectedfrom the group consisting of alkyl, fluoroalkyl, aminoalkyl,N,N-dialkylaminoalkyl and alkylsulfonylalkyl; and said R³ is a hydrogenatom, alkyl or fluoroalkyl group having up to 10 carbon atoms, phenyl,fluorophenyl or chlorophenyl group.
 4. A fluorinated benzodiazepin ofthe formula ##STR24## wherein A¹ and A² are the same or differentgroups, each expressed by one of the following formulas ##STR25##wherein X is a hydrogen atom, methyl group, chlorine atom, or nitrogroup, R¹ is a hydrogen atom, methyl, ethyl, butyl or propyl group, R²is a hydrogen atom, methyl, c-propylmethyl, trifluoroethyl,N,N-diethylaminoethyl, or methylsulfonylethyl group, and R³ is atrifluoromethyl, phenyl, fluorophenyl or chlorophenyl group.